This invention relates to certain substituted 3-cyano-[1,7], [1.5], and [1.8] naphthyridine compounds as well as the pharmaceutically acceptable salts thereof. The compounds of the present invention inhibit the action of certain growth factor receptor protein tyrosine kinases (PTK) and other protein kinases thereby inhibiting the abnormal growth of certain cell types. The compounds of this invention are therefore useful for the treatment of certain diseases that are the result of deregulation of these PTKs. The compounds of this invention are anti-cancer agents and are useful for the treatment of cancer in mammals. In addition, the compounds of this invention are useful for the treatment or inhibition of polycystic kidney disease and colonic polyps in mammals. This invention also relates to the manufacture of said 3-cyano-[1,7], [1.5], and [1.8] naphthyridines, their use for the treatment of cancer and polycystic kidney disease, and the pharmaceutical preparations containing them.
Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine residue located on a protein substrate. Protein tyrosine kinases clearly play a role in normal cell growth. Many of the growth factor receptor proteins function as tyrosine kinases and it is by this process that they effect signaling. The interaction of growth factors with these receptors is a necessary event in normal regulation of cell growth. However, under certain conditions, as a result of either mutation or overexpression, these receptors can become deregulated; the result of this is uncontrolled cell proliferation which can lead to tumor growth and ultimately to the disease known as cancer [Wilks A. F., Adv. Cancer Res., 60, 43 (1993) and Parsons, J. T.; Parsons, S. J., Important Advances in Oncology, DeVita V. T. Ed., J. B. Lippincott Co., Phila., 3 (1993)]. Among the growth factor receptor kinases and their proto-oncogenes that have been identified and which are targets of the compounds of this invention are the epidermal growth factor receptor kinase (EGF-R kinase, the protein product of the erbB oncogene), and the product produced by the erbB-2 (also referred to as the neu or HER2) oncogene. Since the phosphorylation event is a necessary signal for cell division to occur and since overexpressed or mutated kinases have been associated with cancer, an inhibitor of this event, a protein tyrosine kinase inhibitor, will have therapeutic value for the treatment of cancer and other diseases characterized by uncontrolled or abnormal cell growth. For example, overexpression of the receptor kinase product of the erbB-2 oncogene has been associated with human breast and ovarian cancers [Slamon, D. J., et. al., Science, 244, 707 (1989) and Science, 235 , 1146 (1987)]. Deregulation of EGF-R kinase has been associated with epidermoid tumors [Reiss, M., et. al., Cancer Res., 51, 6254 (1991)], breast tumors [Macias, A., et. al., Anticancer Res., 7, 459 (1987)], and tumors involving other major organs [Gullick, W. J., Brit. Med. Bull., 47, 87 (1991)]. Because of the importance of the role played by deregulated receptor kinases in the pathogenesis of cancer, many recent studies have dealt with the development of specific PTK inhibitors as potential anti-cancer therapeutic agents [some recent reviews: Burke. T. R., Drugs Future, 17, 119 (1992) and Chang, C. J.; Geahlen, R. L., J. Nat. Prod., 55, 1529 (1992)]. The compounds of this invention inhibit the kinase activity of EGF-R and are therefore useful for treating certain disease states, such as cancer, that result, at least in part, from deregulation of this receptor. The compounds of this invention are also useful for the treatment and prevention of certain pre-cancerous conditions, such as the growth of colon polyps, that result, at least in part, from deregulation of this receptor.
It is also known that deregulation of EGF receptors is a factor in the growth of epithelial cysts in the disease described as polycystic kidney disease [Du J., Wilson P. D., Amer. J. Physiol., 269(2 Pt 1), 487 (1995); Nauta J., et al., Pediatric Research, 37(6), 755 (1995); Gattone V. H., et al., Developmental. Biology, 169(2), 504 (1995); Wilson P. D., et al., Eur. J. Cell Biol., 61(1), 131, (1993)]. The compounds of this invention, which inhibit the catalytic function of the EGF receptors, are consequently useful for the treatment of this disease.
The mitogen-activated protein kinase (MAPK) pathway is a major pathway in the cellular signal transduction cascade from growth factors to the cell nucleus. The pathway involves kinases at two levels: MAP kinase kinases (MAPKK), and their substrates MAP kinases (MAPK). There are different isoforms in the MAP kinase family. (For review, see Rony Seger and Edwin G. Krebs, FASEB, Vol. 9, 726, June 1995). The compounds of this invention can inhibit the action of two of these kinases: MEK, a MAP kinase kinase, and its substrate ERK, a MAP kinase. MEK is activated by phosphorylation on two serine residues by upstream kinases such as members of the raf family. When activated, MEK catalyzes phosphorylation on a threonine and a tyrosine residue of ERK. The activated ERK then phosphorylates and activates transcription factors in the nucleus, such as fos and jun, or other cellular targets with PXT/SP sequences. ERK, a p42 MAPK is found to be essential for cell proliferation and differentiation. Over-expression and/or over-activation of MEK or ERK has been found to be associated with various human cancers (For example, Vimala S. Sivaraman, Hsien-yu Wang, Gerard J. Nuovo, and Craig C. Malbon, J. Clin. Invest. Vol. 99, No. 7April 1997). It has been demonstrated that inhibition of MEK prevents activation of ERK and subsequent activation of ERK substrates in cells, resulting in inhibition of cell growth stimulation and reversal of the phenotype of ras-transformed cells (David T. Dudley, Long Pang, Stuart J. Decker, Alexander J. Bridges, and Alan R. Saltiel, PNAS, Vol. 92, 7686, August 1995). Since, as demonstrated below, the compounds of this invention can inhibit the coupled action of MEK and ERK, they are useful for the treatment of diseases such as cancer which are characterized by uncontrolled cell proliferation and which, at least in part, depend on the MAPK pathway.
Epithelial Cell Kinase (ECK) is a receptor protein tyrosine kinase (RPTK) belonging to the EPH (Erythropoietin Producing Hepatoma) family. Although originally identified as an epithelial lineage-specific tyrosine kinase, ECK has subsequently been shown to be expressed on vascular endothelial cells, smooth muscle cells, and fibroblasts. ECK is a type I transmembrane glycoprotein with the extracellular ligand-binding domain consisting of a cysteine-rich region followed by three fibronectin type III repeats. The intracellular domain of ECK possesses a tyrosine kinase catalytic domain that initiates a signal transduction cascade reflecting the ECK function. ECK binds and is subsequently activated by its counter-receptor, Ligand for Eph-Related Kinase (LERK)-1, which is an immediate early response gene product readily inducible in a lineage-unrestricted manner with proinflammatory cytokines such as IL-1 or TNF. Soluble LERK-1 has been shown to stimulate angiogenesis in part by stimulating ECK in a murine model of corneal angiogenesis. Unlike their normal counterparts, tumor cells of various lineages constitutively express LERK-1 and this expression can further be upregulated by hypoxia and proinflammatory cytokines. Many of these tumor cells also express ECK at higher levels than their normal counterparts, thereby creating an opportunity for autocrine stimulation via ECK: LERK-1 interaction. The increased expression of both ECK and LERK-1 has been correlated with the transformation of melanomas from the noninvasive horizontal phase of growth into very invasive vertically growing metastatic melanomas. Together, the ECK: LERK-1 interaction is believed to promote tumor growth via its tumor growth promoting and angiogenic effects. Thus, the inhibition of the ECK tyrosine kinase activity mediating signaling cascade induced by its binding and cross-linking to LERK-1 may be therapeutically beneficial in cancer, inflammatory diseases, and hyperproliferative disorders. As is shown below, the compounds of this invention inhibit the tyrosine kinase activity of ECK and are therefore useful for the treatment of the aforementioned disorders.
Growth of most solid tumors is dependent on the angiogenesis involving activation, proliferation and migration of vascular endothelial cells and their subsequent differentiation into capillary tubes. Angiogenization of tumors allows them access to blood-derived oxygen and nutrients, and also provides them adequate perfusion. Hence inhibiting angiogenesis is an important therapeutic strategy in not only cancer but also in a number of chronic diseases such as rheumatoid arthritis, psoriasis, diabetic retinopathy, age-related macular degeneration, and so on. Tumor cells produce a number of angiogenic molecules. Vascular Endothelial Growth Factor (VEGF) is one such angiogenic factor. VEGF, a homodimeric disulfide-linked member of the PDGF family, is an endothelial cell-specific mitogen and is known to cause profound increase in the vascular endothelial permeability in the affected tissues. VEGF is also a senescence-preventing survival factor for endothelial cells. Almost all nucleated tissues in the body possess the capability to express VEGF in response to various stimuli including hypoxia, glucose deprivation, advanced glycation products, inflammatory cytokines, etc. Growth-promoting angiogenic effects of VEGF are mediated predominantly via its signaling receptor Kinase insert Domain containing Receptor (KDR). The expression of KDR is low on most endothelial cells; however, activation with angiogenic agents results in a significant upregulation of KDR on endothelial cells. Most angiogenized blood vessels express high levels of KDR. KDR is a receptor protein tyrosine kinase with an extracellular VEGF-binding domain consisting of 7 immunoglobulin-like domains and a cytoplasmic domain containing the catalytic tyrosine kinase domain split by a kinase-insert region. Binding to VEGF causes dimerization of KDR resulting in its autophosphorylation and initiation of signaling cascade. Tyrosine kinase activity of KDR is essential for mediation of its functional effects as a receptor for VEGF. Inhibition of KDR-mediated functional effects by inhibiting KDR""s catalytic activity is considered to be an important therapeutic strategy in the treatment of disease states such as cancer that depend on blood vessel growth. As is shown below, the compounds of this invention inhibit the tyrosine kinase activity of KDR and are therefore useful for the treatment of the aforementioned disease states.
The Src family of cytoplasmic protein tyrosine kinases consists of at least eight members that participate in a variety of signaling pathways (Schwartzberg, P. L., Oncogene 17: 1463-1468, 1998). The prototypical member of this tyrosine kinase family is p60src (Src). Src is involved in proliferation and migration responses in many cell types. In limited studies, Src activity was found to be elevated in breast, colon (xcx9c90%), pancreatic ( greater than 90%) and liver ( greater than 90%) tumors. Greatly increased Src activity was also associated with metastasis ( greater than 90%) and poor prognosis. Antisense Src message impedes growth of colon tumor cells in nude mice (Staley et al., Cell Growth and Differentiation. 8(3):269-74, 1997), suggesting that Src inhibitors should slow tumor growth. In addition to its role in cell proliferation, Src also acts in stress response pathways, including the hypoxia response, and nude mice studies with colon tumor cells expressing antisense Src message have reduced vascularization (Ellis, et al., J. Biol. Chem., 273(2):1052-7, 1998), which suggests that Src inhibitors would be anti-angiogenic as well as anti-proliferative. The compounds of this invention inhibit Src kinase and are therefore useful for the treatment of disease states that that depend, at least in part, on deregulation of Src kinases.
In addition to the above utilities some of the compounds of this invention are useful for the preparation of other compounds of this invention.
The compounds of this invention are certain substituted 3-cyano-[1.7], [1.5], and [1.8] naphthyridines. Throughout this patent application, the naphthyridines ring systems will be numbered as indicated in the formulas below. 
Some 3-cyano-quinoline derivatives are inhibitors of tyrosine kinases and are described in WO-9843960. The patent U.S. Pat. No. 5,780,482 and application WO-9500511 describe some condensed 4-aminopyridine compounds that have antirheumatic activity and can contain a cyano group at the 3-position. The application WO-9813350 describes some naphthyridines that are inhibitors of VEGF but these inhibitors do not have the important 3-cyano substituent.
Certain quinazoline derivatives are known to be inhibitors of protein tyrosine kinases. The application EP-520722 describes 4-anilinoquinazolines that contain simple substituents such as chloro, trifluoromethyl, or nitro groups at positions 5 to 8. The applications EP-566226 and U.S. Pat. No. 5,616,582 are similar but with a much larger variety of substituents now allowed at positions 5 to 8. The application WO-9609294 describes compounds with similar substituents at positions 5 to 8 and with the substituent at 4-position consisting of some polycyclic ring systems. Some simple substituted quinazolines are also described in the applications WO-9524190, WO-9521613, and WO-9515758. The applications EP-602851 (U.S. Pat. No. 5,580,870) and WO-9523141 cover similar quinazoline derivatives where the aryl group attached at position 4 can be a variety of heterocyclic ring structures. The application EP-635498 and U.S. Pat. No. 5,475,001 describe certain quinazoline derivatives that have alkenoylamino and alkynoylamino groups among the substituents at position 6 and a halogen atom at position 7. The applications WO-9519774 and WO-9823613 describes compounds where one or more of the carbon atoms at positions 5-8 of a quinazoline can be replaced with heteroatoms resulting in a large variety of bicyclic systems where the left-hand ring is a 5 and 6-membered heterocyclic ring; in addition, a variety of substituents are allowed on the left-hand ring. The application EP-682027-A1 describes certain pyrrolopyrimidine inhibitors of PTKs. The application WO-9519970 describes compounds in which the left-hand aromatic ring of the basic quinazoline structure has been replaced with a wide variety of different heterocyclic rings so that the resulting inhibitors are tricyclic.
This invention provides a compound of formula 1: 
wherein:
X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups; or
X is pyridinyl, pyrimidinyl, or Ph; or
X is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms, where the bicyclic heteroaryl ring contains 1 to 4 heteroatoms selected from N, O, and S; wherein the bicyclic aryl or bicyclic heteroaryl ring may be optionally mono-, di-, tri-, or tetra-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino; or
X is the radical 
E is pyridinyl, pyrimidinyl, or Ph;
T is substituted on E at carbon and is
xe2x80x94NH(CH2)m, xe2x80x94O(CH2)mxe2x80x94, xe2x80x94S(CH2)mxe2x80x94, xe2x80x94NR(CH2)mxe2x80x94, xe2x80x94(CH2)mxe2x80x94
xe2x80x94(CH2)mNHxe2x80x94, xe2x80x94(CH2)mOxe2x80x94, xe2x80x94(CH2)mSxe2x80x94, or xe2x80x94(CH2)mNRxe2x80x94; #
L is a Ph; or
L is a 5- or 6-membered heteroaryl ring where the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O, and S; wherein the heteroaryl ring may be optionally mono- or di-substituted with a substituent selected from the group consisting of halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
Pyridinyl, pyrimidinyl, or Ph are pyridinyl, pyrimidinyl, or phenyl radicals, respectively, which may be optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;
Z is xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NRxe2x80x94;
R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms;
Axe2x80x3 is a diavalent moiety selected from the group 
G1, G2, G3, and G4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 2-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulphonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, R2NH, 
xe2x80x83R7xe2x80x94(C(R6)2)gxe2x80x94Yxe2x80x94, R7xe2x80x94(C(R6)2)pxe2x80x94Mxe2x80x94(C(R6)2)kxe2x80x94Yxe2x80x94, Het-(C(R6)2)qxe2x80x94Wxe2x80x94(C(R6)2)kxe2x80x94Yxe2x80x94,
with the proviso that G3 and G4 are not R2NH;
Y is a divalent radical selected from the group consisting of 
R7 is xe2x80x94NR6R6, xe2x80x94OR6, xe2x80x94J, xe2x80x94N(R6)3+, or xe2x80x94NR6(OR6);
M is  greater than NR6, xe2x80x94Oxe2x80x94,  greater than Nxe2x80x94(C(R6)2)pNR6R6, or  greater than Nxe2x80x94(C(R6)2)pxe2x80x94OR6;
W is  greater than NR6, xe2x80x94Oxe2x80x94 or is a bond;
Het is a heterocyclic radical selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4triazole, thiazole, thiazolidine , tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane tetrahydropyran, and 
which may be optionally mono- or di-substituted on carbon with R6, hydroxy, xe2x80x94N(R6)2, xe2x80x94OR6xe2x80x94(C(R)2)sOR6 or xe2x80x94(C(R6)2)sN(R6)2;
optionally mono-substituted on nitrogen with R6; and
optionally mono or di-substituted on a saturated carbon with divalent radicals xe2x80x94Oxe2x80x94 or xe2x80x94O(C(R6)2)sOxe2x80x94;
R6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl 2-7 carbon atoms, phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms; with the proviso that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
R2, is selected from the group consisting of 
R3 is hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, 
xe2x80x83R7xe2x80x94(C(R6)2)sxe2x80x94, R7xe2x80x94(C(R6)2)pxe2x80x94Mxe2x80x94(C(R6)2)rxe2x80x94, R8R9xe2x80x94CHxe2x80x94Mxe2x80x94(C(R6)2)r, or Het-(C(R6)2)qxe2x80x94Wxe2x80x94(C(R6)2)rxe2x80x94;
R5 is hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, 
xe2x80x83R7xe2x80x94(C(R6)2)sxe2x80x94, R7(C(R6)2)pxe2x80x94Mxe2x80x94(C(R6)2)rxe2x80x94, R8R9xe2x80x94CHxe2x80x94Mxe2x80x94(C(R6)2)rxe2x80x94, or Het-(C(R6)2)qxe2x80x94Wxe2x80x94(C(R6)2)rxe2x80x94;
R8, and R9 are each, independently, xe2x80x94(C(R6)2)rNR6R6, or xe2x80x94(C6)2)rOR6;
J is independently hydrogen, chlorine, fluorine, or bromine;
Q is alkyl of 1-6 carbon atoms or hydrogen;
a=0-1;
g=1-6;
k=0-4;
n is 0-1;
m is 0-3;
p=2-4;
q=0-4;
r=1-4;
s=1-6;
u=0-4 and v=0-4, wherein the sum of u+v is 2-4;
or a pharmaceutically acceptable salt thereof,
provided that
when R6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;
and provided that
when R3 is bound to sulfur, it cannot be hydrogen, carboxy, carboalkoxy, or carboalkyl;
and provided that
when Y is xe2x80x94NR6xe2x80x94 and R7 is xe2x80x94NR6R6, xe2x80x94N(R6)3+, or xe2x80x94NR6(OR6), then g=2-6;
when M is xe2x80x94Oxe2x80x94 and R7 is xe2x80x94OR6 then p=1-4;
when Y is xe2x80x94NR6xe2x80x94 then k=2-4;
when Y is xe2x80x94Oxe2x80x94 and M or W is xe2x80x94Oxe2x80x94 then k=1-4
when W is not a bond with Het bonded through a nitrogen atom then q=2-4
and when W is a bond with Het bonded through a nitrogen atom and Y is xe2x80x94Oxe2x80x94 or xe2x80x94NR6xe2x80x94 then k=2-4;
and finally provided that
when Axe2x80x3 is the moiety 
n=0,
Z is NH,
G1 is hydrogen, halogen, alkyl, alkoxy, hydroxy, alkanoyloxy of 2-6 carbon atoms, or phenoxy, and
G2 is hydrogen, halogen, alkyl, hydroxy, carboxyalkyl, carboalkoxyalkyl, hydroxyalkyl, alkoxy, halomethyl, carboxyl, carboalkoxy, alkanoylamino, or alkenoylamino,
then X can not be a pyridinyl, pyrimidinyl, or phenyl ring that is substituted with a hydroxy or alkoxy group.
The pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: acetic, lactic, citric, tartaric, succinic, maleic, malonic, gluconic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
Preferred bicyclic aryl or bicyclic heteroaryl ring systems include naphthalene, 1,2,3,4-tetrahydronaphthalene, tetralin, indane, 1-oxo-indane, 1,2,3,4-tetrahydroquinoline, naphthyridine, benzofuran, 3-oxo-1,3-dihydro-isobenzofuran, benzothiaphene, 1,1-dioxo-benzothiaphene, indole, 2,3-dihydroindole, 1,3-dioxo-2,3-dihydro-1H-isoindole, benzotriazole, 1H-indazole, indoline, benzopyrazole, 1,3-benzodioxole, benzooxazole, purine, phthalimide, coumarin, chromone, quinoline, terahydroquinoline, isoquinoline, benzimidazole, quinazoline, pyrido[2,3-b]pyridine, pyrido[3,4-b]pyrazine, pyrido[3,2-c]pyridazine, pyrido[3,4-b]pyridine, 1H-pyrazole[3,4-d]pyrimidine, 1,4-benzodioxane, pteridine, 2(1H)-quinolone, 1(2H)-isoquinolone, 2-oxo-2,3-dihydro-benzthiazole, 1,2-methylenedioxybenzene, 2-oxindole, 1,4-benzisoxazine, benzothiazole, quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N-oxide, quinazoline-N-oxide, benzoazine, phthalazine, 1,4-dioxo-1,2,3,4-tetrahydro-phthalazine, 2-oxo-1,2-dihydro-quinoline, 2,4-dioxo-1,4-dihydro-2H-benzo [d][1,3]oxazine, 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, or cinnoline.
When L is a 5 or 6-membered heteroaryl ring, preferred heteroaryl rings include pyridine, pyrimidine, imidazole, thiazole, thiazolidine, pyrrole, furan, thiophene, oxazole, or 1,2,4-triazole.
Either or both rings of the bicyclic aryl or bicyclic heteroaryl group may be fully unsaturated, partially saturated, or fully saturated. An oxo substituent on the bicyclic aryl or bicyclic heteroaryl moiety means that one of the carbon atoms has a carbonyl group. A thio substituent on the bicyclic aryl or bicyclic heteroaryl moiety means that one of the carbon atoms has a thiocarbonyl group. When a compound of this invention contains a moiety which contains a heteroaryl ring, such heteroaryl ring does not contain Oxe2x80x94O, Sxe2x80x94S, or Sxe2x80x94O bonds in the ring.
When L is a 5 or 6-membered heteroaryl ring, it may be fully unsaturated, partially saturated, or fully saturated. The heteroaryl ring can be bound to T via carbon or nitrogen. An oxo substituent on the heteroaryl ring means that one of the carbon atoms has a carbonyl group. A thio substituent on the heteroaryl ring means that one of the carbon atoms has a thiocarbonyl group.
The alkyl portion of the alkyl, alkoxy, alkanoyloxy, alkoxymethyl, alkanoyloxymethyl, alkylsulphinyl, alkylsulphonyl, alkylsulfonamido, carboalkoxy, carboalkyl, carboxyalkyl, carboalkoxyalkyl, alkanoylamino, N-alkylcarbamoyl, and N,N-dialkylcarbamoyl , N-alkylaminoalkoxy, N,N-dialkylaminoalkoxy include both straight chain as well as branched carbon chains. The alkenyl portion of the alkenyl, alkenoyloxymethyl, alkenyloxy, alkenylsulfonamido, substituents include both straight chain as well as branched carbon chains and one or more sites of unsaturation and all possible configurational isomers. The alkynyl portion of the alkynyl, alkynoyloxymethyl, alkynylsulfonamido, alkynyloxy, substituents include both straight chain as well as branched carbon chains and one or more sites of unsaturation. Carboxy is defined as a xe2x80x94CO2H radical. Carboalkoxy of 2-7 carbon atoms is defined as a xe2x80x94CO2Rxe2x80x3 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. Carboxyalkyl is defined as a HO2Cxe2x80x94Rxe2x80x2xe2x80x3xe2x80x94 radical where Rxe2x80x2xe2x80x3 is a divalent alkyl radical of 1-6 carbon atoms. Carboalkoxyalkyl is defined as a Rxe2x80x3O2Cxe2x80x94Rxe2x80x2xe2x80x3xe2x80x94 radical where Rxe2x80x2xe2x80x3 is a divalent akyl radical and where Rxe2x80x3 and Rxe2x80x2xe2x80x3 together have 2-7 carbon atoms. Carboalkyl is defined as a xe2x80x94CORxe2x80x3 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. Alkanoyloxy is defined as a xe2x80x94OCORxe2x80x3 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. Alkanoyloxymethyl is defined as Rxe2x80x3CO2CH2xe2x80x94 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. Alkoxymethyl is defined as Rxe2x80x3OCH2xe2x80x94 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. Alkylsulphinyl is defined as Rxe2x80x3SOxe2x80x94 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. Alkylsulphonyl is defined as Rxe2x80x3SO2-radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. Alkylsulfonamido, alkenylsulfonamido, alkynylsulfonamido are defined as Rxe2x80x3SO2NHxe2x80x94 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms, an alkenyl radical of 2-6 carbon atoms, or an alkynyl radical of 2-6 carbon atoms, respectively. N-alkylcarbamoyl is defined as Rxe2x80x3NHCOxe2x80x94 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. N,N-dialkylcarbamoyl is defined as Rxe2x80x3 Rxe2x80x2NCOxe2x80x94 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms, Rxe2x80x2 is an alkyl radical of 1-6 carbon atoms and Rxe2x80x2, and Rxe2x80x3 may be the same or different. When X is substituted, it is preferred that it is mono- , di- , or tri-substituted, with mono- and di-substituted being most preferred. It is preferred that of the substituents G3 and G4, at least one is hydrogen and it is most preferred that both be hydrogen. It is also preferred that X is a phenyl ring, Z is xe2x80x94NHxe2x80x94, and n=0.
Het is a heterocycle, as defined above which may be optionally mono- or di-substituted on carbon with R6, optionally mono-substituted on nitrogen with R6, optionally mono- or di-substituted on carbon with hydroxy, xe2x80x94N(R6)2, or xe2x80x94OR6, optionally mono or di-substituted on carbon with xe2x80x94(C(R6)2)sOR6 or xe2x80x94(C(R6)2)sN(R6)2, and optionally mono or di-substituted on a saturated carbon with divalent xe2x80x94Oxe2x80x94 or xe2x80x94O(C(R6)2)sOxe2x80x94 (carbonyl and ketal groups, respectively); in some cases when Het is substituted with xe2x80x94Oxe2x80x94 (carbonyl), the carbonyl group can be hydrated. Het may be bonded to W when q=0 via a carbon atom on the heterocyclic ring, or when Het is a nitrogen containing heterocycle which also contains a saturated carbon-nitrogen bond, such heterocycle may be bonded to carbon, via the nitrogen when W is a bond. When q=0 and Het is a nitrogen containing heterocycle which also contains an unsaturated carbon-nitrogen bond, that nitrogen atom of the heterocycle may be bonded to carbon when W is a bond and the resulting heterocycle will bear a positive charge. When Het is substituted with R6, such substitution may be on a ring carbon, or in the case of a nitrogen containing heterocycle, which also contains a saturated carbon-nitrogen, such nitrogen may be substituted with R6 or in the case of a nitrogen containing heterocycle, which also contains an unsaturated carbon-nitrogen, such nitrogen may be substituted with R6 in with case the heterocycle will bear a positive charge. Preferred heterocycles include pyridine, 2,6-disubstituted morpholine, 2,5-disubstituted thiomorpholine, 2-substituted imidazole, substituted thiazole, N-substituted imidazole, N-subsitituted 1,4-piperazine, N-subsitituted piperadine, and N-substituted pyrrolidine.
The compounds of this invention may contain one or more asymmetric carbon atoms; in such cases, the compounds of this invention include the individual diasteromers, the racemates, and the individual R and S entantiomers thereof. Some of the compound of this invention may contain one or more double bonds; in such cases, the compounds of this invention include each of the possible configurational isomers as well as mixtures of these isomers. When a compound of this invention contains a moiety containing the same substituent more than once (for example, when R7 is xe2x80x94NR6R6), each substituent (R6, in this example) may be the same or different.
The compounds of this invention can be prepared from commercially available starting materials or starting materials which can be prepared using literature procedures. More specifically, the preparation of the compounds and intermediates of this invention encompassed by Formulas 8a-c is described below in Flowsheet 1 where X, n, G2, G1, and G4 are as described above. The reaction of 2 with a chlorinating reagent such as thionyl chloride or oxalyl chloride in methylene chloride using dimethylformamide as a catalyst gives the acid chlorides of formula 3. Condensation of 3 with reagent 4 in refluxing methylene chloride gives intermediate 5. Heating 5 with ammonium hydroxide in ethanol gives the quinolone 6 or the corresponding hydroxy naphthyridine tautomer. Chlorination with phosphorous oxychloride or oxalyl chloride furnishes 7. Condensation of 7 with various amines, anilines, alcohols, phenols, mercaptans, and thiophenols give the compounds of this invention 8a-c. Thus, 7 can be reacted with an amine or aniline by heating in an inert solvent such as tetrahydrofuran, butanol, or methoxyethanol to give compounds of Formula 8a where Z is xe2x80x94NHxe2x80x94. The reaction of 7 with a mercaptan or thiophenol in an inert solvent can be accomplished using a base such as sodium hydride to give compounds of Formula 8c where Z is xe2x80x94Sxe2x80x94. The reaction of 7 with an alcohol or phenol in an inert solvent can be accomplished using a base such as sodium hydride to give compounds of Formula 8b where Z is xe2x80x94Oxe2x80x94. 
The preparation of the compounds of this invention encompassed by Formula 12, which are important intermediates for the preparation of other compounds of this invention, is described below in Flowsheet 2 where Z, X, n, G2 and G4 are as described above. Nitration of 9 with fuming nitric acid and sulfuric acid followed by chlorination 5 with refluxing phosphorous oxychloride gives 10. By using the methods described above in Flowsheet 1, 10 is converted to compounds represented by formula 11. Reduction of 11 with iron and ammonium chloride in a water-methanol mixture, at reflux, gives the compounds of this invention represented by formula 12. Compound 12, in turn, can be used to prepare other compounds of this invention. 
The preparation of the compounds and intermediates of this invention encompassed by Formulas 19a-c is described below in Flowsheet 3 where X, n, G1, G3, and G4 are as described above. Reduction of the nitro group of 13 using hydrogen and a nickel catalyst followed by protection of the amino group as a t-butoxycarbonatederivative (BOC group) gives 14. Lithiation of 14 in ether using n-butyl lithium occurs at low temperature. Trapping with carbon dioxide followed by acidification gives a carboxylic acid which can be converted to the methyl ester by treatment with trimethylsilyl diazomethane in methanol. Alternatively, the lithiated species can be reacted with ethylchloroformate to give 15 directly. The lithium enolate of acetonitrile is prepare in tetrahydrofuran by addition of acetonitrile to a cold solution of n-butyl lithium. Addition of a tetrahydrofuran solution of 15 to the solution of lithio acetonitrile at low temperature gives, after work up, compound 16. The reaction of 16 with dimethylformamide dimethylacetal gives the hydroxy naphthyridine intermediate 17 or a tautomer thereof. Chlorination with phosphorous oxychloride or oxalyl chloride furnishes 18. Condensation of 18 with various amines, anilines, alcohols, phenols, mercaptans, and thiophenols give the compounds of this invention 19a-c. 
The preparation of the compounds of this invention encompassed by Formulas 22a-d, which are important intermediates for the preparation of other compounds of this invention, is described below in Flowsheet 4 where Z, X, n, G3, and G4 are as described above and Jxe2x80x3 is fluorine or chlorine. The chloropyridine 20a can be converted to the corresponding fluoropyridine 20b by heating a solution of it with KF in dimethylsulfoxide. By using the methods describes above in Flowsheet 3, 20 is converted to compounds represented by formula 21. The fluoride atom of 21 can be displaced with p-methoxybenzylamino group by heating with p-methoxybenzylamine in an inert solvent. Cleavage of the p-methoxybenzylamino group using trifluoroacetic acid gives the 6-amino derivative 22a. Condensation of 21 with various other amines, anilines, alcohols, phenols, mercaptans, and thiophenols (some of which are listed in Lists A and B below) give the compounds of this invention 22b-d. 
The preparation of the compounds and intermediates of this invention encompassed by Formulas 29a-c is described below in Flowsheet 5 where X, n, G., G2, and G3 are as described above. The nitro group of 23 can be reduced to the amino group by catalytic hydrogenation in an inert solvent. The condensation of 24 and the reagent 25 by heating in the absence of solvent gives 26. Thermal cyclization of 26 in refluxing Dowtherm or diphenyl ether gives the compound 27 or its corresponding tautomer. Chlorination of 27 in refluxing phosphorous oxychloride furnishes 28. Condensation of 28 with various amines, anilines, alcohols, phenols, mercaptans, and thiophenols gives the compounds of this invention 29a-c. 
The preparation of the compounds of this invention encompassed by Formula 32, which are important intermediates for the preparation of other compounds of this invention, is described below in Flowsheet 6 where Z, X, n, G2 and G3 are as described above. Starting with compounds 30 where the amino group is protected as its acetate derivative and using the methods outlined above in Scheme 5, the compounds represented by formula 31 are obtained. Condensation of 31 with various amines, anilines, alcohols, phenols, mercaptans, and thiophenols as described in Flowsheet 5 gives the compounds of this invention 32. The conditions of these condensation reactions also results in removal of the acetate protecting group. 
The preparation of the compounds of this invention encompassed by Formulas 36, 38, and 40 is described below in Flowsheet 7 wherein G2, G3, G4, Z, n, and X are defined. R10 is alkyl of 1-6 carbon atoms (preferably isobutyl). R2xe2x80x2 is a radical selected from the group consisting of: 
wherein R6, R3, R5, J, s, r, u, and v are defined. According to the reactions outlined in Flowsheet 7, acylation of 33 with either an acid chloride of Formula 34 or a mixed anhydride of Formula 35 (which is prepared from the corresponding carboxylic acid) in an inert solvent such as tetrahydrofuran (THE) in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine, or N-methyl morpholine gives the compounds of this invention of Formula 36. In those cases where 34 or 35 have an asymmetric carbon atom, they can be used as the racemate or as the individual R or S entantiomers in which case the compounds of this invention will be in the racemic or R and S optically active forms, respectively. In those cases, where the R2xe2x80x2 contains primary or secondary amino groups, the amino groups will first have to be protected prior to anhydride or acid chloride formation. Suitable protecting groups include, but are not limited to, tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ) protecting groups. The former protecting group can be removed from the final products by treatment with an acid such as trifluoroactic acid while the latter protecting group can be removed by catalytic hydrogenation. In those cases where the R2xe2x80x2 contains hydroxyl groups, the hydroxyl groups may first have to be protected prior to anhydride or acid chloride formation. Suitable protecting groups include, but are not limited to, t-butyldimethylsilyl, tetrahydropyranyl, or benzyl protecting groups. The first two protecting groups can be removed from the final products by treatment with an acid such as acetic acid or hydrochloric acid while the latter protecting group can be removed by catalytic hydrogenation. In those cases, in intermediates 33, 37, or 39 where X contains primary or secondary amino groups or hydroxyl groups, it may be necessary to protect these groups prior to the reaction with 34 or 35. The same amine or alcohol protecting groups describe above can be used and they can be removed from the products as previously described. In a similar manner, 37 can be converted to 38 and 39 can be converted to 40. 
By using methods similar to that describe above in Flowsheet 7, the intermediates 41 can be converted to the compounds of this invention, 42. The analogous [1.8]-naphthyridine can be prepared in the same way. 
In order to prepare the compounds of this invention, certain amines are required. Some representative amines are shown below in List A wherein R6, p, and r are as defined above. These amines are available commercially, are known in the chemical literature, or can be prepared by simple procedures that are well known in the art. In some cases, these amines may have one or more asymmetric carbon atoms; they can be used as the racemate or they can be resolved and used as the individual R or S entantiomers in which case the compounds of this invention will be in the racemic or optically active forms, respectively. Throughout this application in the Flowsheets shown below, these amines, and other similar amines, will be represented by the generic structure of the formula:
(Rxe2x80x2)2NH, wherein this formula can represent a primary or secondary amine. 
In order to prepare the compounds of this invention certain alcohols are required. Some representative alcohols are shown below in List B wherein R6, p, and r are as defined above. These alcohols are available commercially, are known in the chemical literature, or can be prepared by simple procedures that are well known in the art. In some cases, these alcohols may have one or more asymmetric carbon atoms; they can be used as the racemate or they can be resolved and used as the individual R or S entantiomers in which case the compounds of this invention will be in the racemic or optically active forms, respectively. Throughout this application in the Flowsheets shown below, these alcohols, and other similar alcohols, will be represented by the generic structure of the formula:
Rxe2x80x2OH

In order to prepare some of the compounds of this invention certain mixed anhydrides are required; these are prepared as outlined below in the following Flowsheets wherein R6, R10, X, Z, n, and s are as defined above. Jxe2x80x2 is a halogen atom chlorine, bromine, or iodine, or is a toslyate (p-toluenesulfonate) or mesylate (methanesulfonate) group. The reaction of 43 with an amine of List A is accomplished by heating in an inert solvent such as tetrahydrofuran or N,N-dimethylformamide, or using potassium or cesium carbonate in acetone. The temperature and duration of the heating will depend on the reactivity of 43; longer reaction times and higher temperatures may be required when s is greater than 1. Treatment of 44 with an alkyl lithium reagent followed by quenching with an atmosphere of dry carbon dioxide furnishes the carboxylic acids of formula 45. These can be converted to mixed anhydrides of Formula 47 using a reagent such as isobutylchloroformate in an inert solvent such as tetrahydrofuran in the presence of a base such as N-methylmorpholine. These anhydrides can then be used to prepare the compounds of this invention as described in the above flowsheets. The reaction of 43 with an alcohol of List B is accomplished using sodium hydride or other non-nucleophic base such as potassium or cesium carbonate in an inert solvent such as tetrahydrofuran, acetone, or N,N-dimethylformamide. In some cases, the alcohol of List B can also be the solvent of the reaction. Treatment of 48 with an alkyl lithium reagent followed by quenching with an atmosphere of dry carbon dioxide furnishes the carboxylic acids of formula 49. These can be converted to mixed anhydrides formula 50 using a reagent such as isobutylchloroformate in an inert solvent such as tetrahydrofuran in the presence of a base such as N-methylmorpholine. These anhydrides can then be used to prepare the compounds of this invention as described in the above flowsheets. 
As outline in Flowsheet 9 below wherein G2, G3, G4, R6, R10, X, Z, n, and s are as defined above, alcohols 51 can be protected with a t-butyl dimethysilyl protecting group by the reaction with the respective silyl chloride in methylene chloride in the presence of triethylamine and 4-N,N-dimethylamino pyridine (DMAP). The resulting protected alcohols, 52, are converted to the acetylenic Grignard reagents which, in turn, are maintained under an atmosphere of dry carbon dioxide to give the carboxylic acids 53. As described above these are converted to the mixed anhydrides 55 which on reaction with the 6-amino-[1,7] naphthyridine 56 gives 57. In the final step of the sequence, the silyl protecting group is removed by treating with acid in a protic solvent mixture to give the compounds represented by Formula 58. In the same manner the corresponding [1.8] naphthyridine 59 and the [1.5] naphthyridine 60 can be prepared. 
Compounds of this invention are also prepared as shown below in Flowsheet 10 wherein G2, G3, G4, R6, RIO, X, Z, n, and s are as defined above. Jxe2x80x2 is chlorine, bromine, or iodine, or is a toslyate or mesylate group. Treatment of 61 with an alkyl lithium reagent at low temperature followed by quenching with an atmosphere of dry carbon dioxide furnishes the carboxylic acids of formula 62. These can be converted to mixed anhydrides of Formula 63 using a reagent such as isobutylchloroformate in an inert solvent such as tetrahydrofuran in the presence of a base such as N-methylmorpholine. These anhydrides can then be used to prepare the compounds of this invention as by the reaction with the 6-amino-[1,7] naphthyridine 64 described above in the Flowsheets. The reaction of 65 with an alcohol of List B is accomplished using sodium hydride or other non-nucleophic base in an inert solvent such as tetrahydrofuran or N,N-dimethylformamide to give the compounds of this invention represented by 66. In some cases, the alcohol of List B can also be the solvent of the reaction. The reaction of 65 with an amine of List A gives the compounds of this invention represented by 67 is accomplished by heating in an inert solvent such as tetrahydrofuran or N,N-dimethylformamide, or using potassium or cesium carbonate in acetone. The temperature and duration of the heating will depend on the reactivity of 65; longer reaction times and higher temperatures may be required when s is greater than 1. 
Using methods similar to that summarized above the [1.5] naphthyridines 68-70 and the [1.8] naphthyridines 71 and 72 can be prepared. 
Other carboxylic acid chlorides and anhydrides needed to prepare some of the compounds of the invention are prepared as shown below in Flowsheet 11 wherein R6, R3, R10, X, Z, Jxe2x80x2, n, and s are as defined above. Qxe2x80x2 is an alkyl group of 1-6 carbon atoms. The esters 73, 77, or 82 can be hydrolyzed with a base such as barium hydroxide to give the respective carboxylic acid 74, 78, or 83. These acid can be converted to the respective carboxylic acid chlorides 75 or 80 by using oxalyl chloride and catalytic N,N-dimethylformamide in an inert solvent or respective mixed anhydrides 79 or 84 by using isobutyl chloroformate and an organic base such as N-methylmorpholine. The leaving group Jxe2x80x2 in compounds represented by Formula 81 and 76 can be displaced by the amines of List A or the alcohols of List B by using procedures previously described to give the intermediates 82 and 77, respectively. The carboxylic acid chlorides 75 and 80 and the anhydrides 79 and 84 can be used to prepare some of the compounds of this invention by using the methods outlined herein above in the Flowsheets. 
By using the methods identical to those outlined above in Flowsheet 11, it is possible to prepare the analogous carboxylic acid chlorides and anhydrides given below in List C wherein R6, R3, p, and s are as previously defined. G is the radical: 
and A is the radical:
xe2x80x94N(Rxe2x80x2)2, xe2x80x94Oxe2x80x2, or xe2x80x94Jxe2x80x2
wherein xe2x80x94N(Rxe2x80x2)2 is derived from the amines of List A, xe2x80x94ORxe2x80x2 are derived from the alcohols of List B, and Jxe2x80x2 is a leaving group as defined previously. By making use of these carboxylic acid chlorides and anhydrides, by following the methods summarized in the above in Flowsheets, and by pursuing the details described in the examples given below, many of the compounds of this invention can be prepared. 
Compounds of this invention represented by Formulas 88-95 can be prepared as shown in Flowsheet 12 wherein G1, G2, G3, G4, R6, R10, X, Z, Jxe2x80x2, n, and s are as defined above. The reaction of the carboxylic acid chlorides 85 and the 6-amino-[1,7] naphthyridines 86 using an organic base in an inert solvent gives the compounds of this invention represented by Formula 87. The reaction of 87 with an alcohol of List B is accomplished using sodium hydride or other non-nucleophic base such as potassium or cesium carbonate in an inert solvent such as tetrahydrofuran, acetone, or N,N-dimethylformamide to give the compounds of this invention represented by 88. In some cases, the alcohol of List B can also be the solvent of the reaction. The reaction of 87 with an amine of List A to give the compounds of this invention represented by 89 is accomplished by heating in an inert solvent such as tetrahydrofuran or N,N-dimethylformamide. The temperature and duration of the heating will depend on the reactivity of 87; longer reaction times and higher temperatures may be required when s is greater than 1. In addition, by using this method, the carboxylic acid chlorides and mixed anhydrides listed in List C can be used to prepare the analogous compounds of this invention. By applying the methods summarized above, The corresponding [1.8]-naphthyridines 90 and 91 and the corresponding [1.5]-naphthyridines 92-95 can be prepared. 
The reaction of 96 with a nitrogen containing heterocycle BET which also contains an unsaturated carbon-nitrogen bond is accomplished by refluxing in an inert solvent and gives the [1,7]-naphthyridines compounds 97 of this invention where the compound bears a positive charge. The counter anion Jxe2x80x2 can be replaced with any other pharmaceutically acceptable anion using the appropriate ion exchange resin. The corresponding [1.8]-naphthyridines and [1.5]-naphthyridines can be prepared in an analogous manner. 
Some of the compounds of this invention can be prepared as outline below in Flowsheet 13 wherein G3, G4, R6, R10, X, Z, J, n, and r are as defined above. The acetylenic alcohols 98 can be coupled to the halides, mesylates, or tosylates 99 using a base such as sodium hydride in an inert solvent such as tetrahydrofuran. The resulting acetylene, 100, is then treated with an alkyl lithium reagent at low temperature. Maintaining the reaction under an atmosphere of carbon dioxide then gives the carboxylic acids 101. These, in turn, are reacted with the 6-amino-[1.7]-naphthyridines, 102, via the mixed anhydrides to give the compounds of this invention represented by Formula 103. Alternatively, the intermediates 106 can be prepared starting with an alcohol 104 by first treating it with a base such as sodium hydride in an inert solvent such as tetrahydrofuran and then adding an acetylene 105 that has an appropriate leaving group. In a similar manner, the amino alcohols represented by the formula: (R6)2Nxe2x80x94(C(R6)2)rxe2x80x94OH by reacting with 105 can be converted to the compounds of this invention represented by the formula 107. In an entirely analogous manner the corresponding [1.5] and [1.8]-naphthyridines are prepared. 
The compounds of this invention represented by Formula 111 and 112 are prepared as shown below in Flowsheet 14 wherein G3, G4, R6, and n defined above and the amines HN(Rxe2x80x3)2 are selected from the group: 
Refluxing 108 and 109 in a solvent such as ethanol gives the intermediate 110 which can react with an amine in refluxing ethanol to give the compounds of this invention represented by Formula 112. Treating 110 with an excess of a sodium alkoxide in an inert solvent or a solvent from which the alkoxide is derived gives the compounds of this invention of Formula 111. In an entirely analogous manner the corresponding [1.5] and [1.8]-naphthyridines are prepared. 
Compounds of this invention represented by Formula 118 can be prepared as shown in Flowsheet 15 wherein G3, G4, R6, R3, R10, X, Z, n, and r are as defined above. The reaction of the mecapto carboxylic acids 113 with the reagents 114 give the compounds represented by Formula 115. Alternatively, 115 can be prepared from the mercaptan R3SH using the mercapto acid 113, triethylamine and 2,2xe2x80x2-dipyridyl disulfide. Mixed anhydride formation to give 116 followed by condensation with the 6-amino-[1,7]-naphthyridines 117 give the compounds of this invention. In an entirely analogous manner the corresponding [1.5] and [1.8]-naphthyridines are prepared. 
Compounds of this invention represented by Formulas 121-123 can be prepared as shown in Flowsheet 16 wherein G3, G4, R5, Jxe2x80x2, X, Z, and n are as defined above. Qxe2x80x2 is alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, or hydrogen. Akylation of 119 with the 6-amino-[1,7]-naphthyridines 120 can be accomplished by heating in an inert solvent such as N,N-dimethylformamide using a base such as potassium carbonate to give the compounds of this invention represented by the Formula 121. When Qxe2x80x2 is alkoxy, the ester group can be hydrolyzed to an acid using a base such as sodium hydroxide in methanol. In a similar manner, by using intermediates 124 and 125, the compounds of this invention represented by Formulas 122 and 123 can be prepared, respectively. In an entirely analogous manner the corresponding [1.5] and [1.8]-naphthyridines are prepared. 
Compounds of this invention represented by Formula 128 can be prepared as shown in Flowsheet 17 wherein G3, G4, R5, X, Z, and n are as defined above. The reaction of reagent 126 with the 6-amino-[1,7]-naphthyridines 127 is accomplished using an excess of an organic base such as triethylamine and an inert solvent such as tetrahydrofuran to give compounds of this invention represented by Formula 128. In an entirely analogous manner the corresponding [1.5] and [1.8]-naphthyridines are prepared. 
With respect to the above Flowsheets 1-17, in those cases where G1, G2, G3, G4, or other substituent may contain an asymmetric carbon atom, the intermediates can be used as the racemate or as the individual R or S entantiomers in which case the compounds of this invention will be in the racemic or R and S optically active forms, respectively. In cases where the substituents may contribute more than one asymmetric carbon atom, diasteriomers may be present; these can be separated by methods well known in the art including, but not limited to, fractional crystallization and chromatographic methods. In those cases where G1, G2, G3, G4, or other substituents contain primary or secondary amino groups, the amino groups may first have to be used in protected form prior to applying the chemistry described in the above Flowsheets. Suitable protecting groups include, but are not limited to, tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ) protecting groups. The former protecting group can be removed from the final products by treatment with an acid such as trifluoroactic acid while the latter protecting group can be removed by catalytic hydrogenation. In those cases where the G1, G2, G3, G4, or other substituents contain hydroxyl groups, the hydroxyl groups may first have to be used in protected form prior to applying the chemistry described in the above Flowsheets. Suitable protecting groups include, but are not limited to, t-butyldimethylsilyl, tetrahydropyranyl, or benzyl protecting groups. The first two protecting groups can be removed from the final products by treatment with an acid such as acetic acid, hydrofluoric acid, or hydrochloric acid while the latter protecting group can be removed by catalytic hydrogenation.
There are certain functional group manipulations that are useful to prepare the compounds of this invention that can be applied to various intermediate 3-cyano-naphthyridines as well as to the final compounds of this invention. These manipulations refer to the substituents G1, G2, G3, or G4 that are located on the 3-cyano-naphthyridines shown in the above Flowsheets. Some of these functional group manipulations are described below:
Where one or more of G0, G2, G3, or G4is a nitro group, it can be converted to the corresponding amino group by reduction using a reducing agent such as iron in acetic acid or by catalytic hydrogenation. Where one or more of G1, G2, G3, or G4is an amino group, it can be converted to the corresponding dialkyamino group of 2 to 12 carbon atoms by alkylation with at least two equivalents of an alkyl halide of 1 to 6 carbon atoms by heating in an inert solvent or by reductive alkylation using an aldehyde of 1 to 6 carbon atoms and a reducing agent such as sodium cyanoborohydride. Where one or more of G1, G2, G3, or G4is a methoxy group, it can be converted to the corresponding hydroxy group by reaction with a demethylating agent such as boron tribromide in an inert solvent or by heating with pyridinium chloride with or without solvent. Where one or more of G1, G2, G3, or G4is an amino group, it can be converted to the corresponding alkylsulfonamido, alkkenylsulfonamido, or alkynylsulfonamido group of 2 to 6 carbon atoms by the reaction with an alkylsulfonyl chloride, alkenylsulfonyl chloride, or alkynylsulfonyl chloride, respectively, in an inert solvent using a basic catalyst such as triethylamine or pyridine. Where one or more of G1, G2, G3, or G4is an amino group, it can be converted to the corresponding alkyamino group of 1 to 6 carbon atoms by alkylation with one equivalent of an alkyl halide of 1 to 6 carbon atoms by heating in an inert solvent or by reductive alkylation using an aldehyde of 1 to 6 carbon atoms and a reducing agent such as sodium cyanoborohydride in a protic solvent such as water or alcohol, or mixtures thereof. Where one or more of G0, G2, G3, or G4 is hydroxy, it can be converted to the corresponding alkanoyloxy, group of 1-6 carbon atoms by reaction with an appropriate carboxylic acid chloride, anhydride, or mixed anhydride in a inert solvent using pyridine or a trialkylamine as a catalyst. Where one or more of G1, G2, G3, or G4 is hydroxy, it can be converted to the corresponding alkenoyloxy group of 1-6 carbon atoms by reaction with an appropriate carboxylic acid chloride, anhydride, or mixed anhydride in an inert solvent using pyridine or a trialkylamine as a catalyst. Where one or more of G1, G2, G3, or G4 is hydroxy, it can be converted to the corresponding alkynoyloxy group of 1-6 carbon atoms by reaction with an appropriate carboxylic acid chloride, anhydride, or mixed anhydride in a inert solvent using pyridine or a trialkylamine as a catalyst. Where one or more of G1, G2, G3, or G4 is carboxy or a carboalkoxy group of 2-7 carbon atoms, it can be converted to the corresponding hydroxymethyl group by reduction with an appropriate reducing agent such as borane, lithium borohydride, or lithium aluminum hydride in a inert solvent; the hydroxymethyl group, in turn, can be converted to the corresponding halomethyl group by reaction in an inert solvent with a halogenating reagent such as phosphorous tribromide to give a bromomethyl group, or phosphorous pentachloride to give a chloromethyl group. The hydroxymethyl group can be acylated with an appropriate acid chloride, anhydride, or mixed anhydride in an inert solvent using pyridine or a trialkylamine as a catalyst to give the compounds of this invention with the corresponding alkanoyloxymethyl group of 2-7 carbon atoms, alkenoyloxymethyl group of 2-7 carbon atoms, or alkynoyloxymethyl group of 2-7 carbon atoms. Where one or more of G1, G2, G3, or G4 is a halomethyl group, it can be converted to an alkoxymethyl group of 2-7 carbon atoms by displacing the halogen atom with a sodium alkoxide in an inert solvent. Where one or more of G1, G2, G3, or G4 is a halomethyl group, it can be converted to an aminomethyl group, N-alkylaminomethyl group of 2-7 carbon atoms or N,N-dialkylaminomethyl group of 3-14 carbon atoms by displacing the halogen atom with ammonia, a primary, or secondary amine, respectively, in an inert solvent.
In addition to the methods described herein above and in the examples below, WO-9843960 describes methods that are useful for the preparation of the compounds of this invention. In addition there are some patent applications that describe the preparation of certain quinazolines, many of the synthetic methods therein are applicable to the preparation of substituted 3-cyano-[1,7], [1.5], and [1 8] naphthyridines of this invention. The chemical procedures described in the application WO-9633981 can be used to prepare the naphthyridine intermediates used in this invention wherein G1, G2, G3, or G4 are alkoxyalkylamino groups. The chemical procedures described in the application WO-9633980 can be used to prepare the 3-cyano-naphthyridine intermediates used in this invention wherein G1, G3, G2, or G4 are aminoalkylalkoxy groups. The chemical procedures described in the application WO-9633979 can be used to prepare the naphthyridine intermediates used in this invention wherein G1, G3, G2, or G4 are alkoxyalkylamino groups. The chemical procedures described in the application WO-9633978 can be used to prepare the naphthyridine intermediates used in this invention wherein G1, G3, G2, or G4 are aminoalkylamino groups. The chemical procedures described in the application WO-9633977 can be used to prepare the naphthyridineintermediates used in this invention wherein G1, G3, G2, or G4 are aminoalkylalkoxy groups. Although the above patent applications describe compounds where the indicated functional group have been introduced onto the 6-position of a quinazoline, the same chemistry can be used to introduce the same groups unto positions occupied by the G1, G3, G2, and G4 substituents of the naphthyridine compounds of this invention.
Representative compounds of this invention were evaluated in several standard pharmacological test procedures that showed that the compounds of this invention possess significant activity as inhibitors of protein tyrosine kinase and are antiproliferative agents. Based on the activity shown in the standard pharmacological test procedures, the compounds of this invention are therefore useful as antineoplastic agents. The test procedures used and results obtained are shown below.
Representative test compounds were evaluated for their ability to inhibit the phosphorylation of the tyrosine residue of a peptide substrate catalyzed by the enzyme epidermal growth factor receptor kinase. The peptide substrate (RR-SRC) has the sequence arg-arg-leu-ile-glu-asp-ala-glu-tyr-ala-ala-arg-gly. The enzyme used in this assay is the His-tagged cytoplasmic domain of EGFR. A recombinant baculovirus (vHcEGFR52) was constructed containing the EGFR cDNA encoding amino acids 645-1186 preceded by Met-Ala-(His)6. Sf9 cells in 100 mm plates were infected at an moi of 10 pfu/cell and cells were harvested 48 h post infection. A cytoplasmic extract was prepared using 1% Triton X-100 and applied to Ni-NTA column. After washing the column with 20 mM imidazole, HcEGFR was eluted with 250 mM imidazole (in 50 mM Na2HPO4, pH 8.0, 300 mM NaCl). Fractions collected were dialyzed against 10 mM HEPES, pH 7.0, 50 mM NaCl, 10% glycerol, 1 ug/mL antipain and leupeptin and 0.1 mM Pefabloc SC. The protein was frozen in dry ice/methanol and stored xe2x88x9270xc2x0 C.
Test compounds were made into 10 mg/m stock solutions in 100% dimethylsulfoxide (DMSO). Prior to experiment, stock solutions were diluted to 500 uM with 100% DMSO and then serially diluted to the desired concentration with HEPES buffer (30 mM HEPES pH 7.4).
For the enzyme reaction, 10 uL of each inhibitor (at various concentrations) were added to each well of a 96-well plate. To this was added 3 uL of enzyme (1:10 dilution in 10 mM HEPES, pH 7.4 for final conc. of 1:120). This was allowed to sit for 10 min on ice and was followed by the addition of 5 ul peptide (80 uM final conc.), xe2x88x9210 ul of 4xc3x97 Buffer (Table A), 0.25 uL 33P-ATP and 12 uL H2O. The reaction was allowed to run for 90 min at room temperature and was followed by spotting the entire volume on to precut P81 filter papers. The filter discs were washed 2xc3x97 with 0.5% phosphoric acid and radioactivity was measured using a liquid scintillation counter.
The inhibition data for representative compounds of the invention are shown below in TABLE 1. The IC50 is the concentration of test compound needed to reduce the total amount of phosphorylated substrate by 50%. The % inhibition of the test compound was determined for at least three different concentrations and the IC50 value was evaluated from the dose response curve. The % inhibition was evaluated with the following formula:
% inhibition=100-[CPM(drug)/CPM(control)]xc3x97100 
where CPM(drug) is in units of counts per minute and is a number expressing the amount of radiolabeled ATP (xcex3-33P) incorporated onto the RR-SRC peptide substrate by the enzyme after 90 minutes at room temperature in the presence of test compound as measured by liquid scintillation counting. CPM(control) is in units of counts per minute and was a number expressing the amount of radiolabeled ATP (xcex3-33P) incorporated into the RR-SRC peptide substrate by the enzyme after 90 minutes at room temperature in the absence of test compound as measured by liquid scintillation counting. The CPM values were corrected for the background counts produced by ATP in the absence of the enzymatic reaction; Where it was possible to determine an, IC50 value, this is reported in TABLE 1 otherwise the % inhibition at 0.5 xcexcM concentration of test compound is shown in TABLE 1.
Inhibition of Epithelial Cell Kinase (ECK)
In this standard pharmacological test procedure, a biotinylated peptide substrate is first immobilized on neutravidin-coated microtiter plates. The test drug, the Epithelial Cell Kinase (ECK), Mg++, sodium vanadate (a protein tyrosine phosphatase inhibitor), and an appropriate buffer to maintain pH (7.2) are then added to the immobilized substrate-containing microtiter wells. ATP is then added to initiate phosphorylation. After incubation, the assay plates are washed with a suitable buffer leaving behind phosphorylated peptide which is exposed to horse radish peroxidase (HRP)-conjugated anti-phosphotyrosine monoclonal antibody. The antibody-treated plates are washed again and the HRP activity in individual wells is quantified as a reflection of degree of substrate phosphorylation. This nonradioactive format was used to identify inhibitors of ECK tyrosine kinase activity where the IC50 is the concentration of drug that inhibits substrate phosphorylation by 50%. The results obtained for representative compounds of this invention are listed in TABLE 2. Multiple entries for a given compound indication it was tested multiple times.
Inhibition of Kinase Insert Domain Containing Receptor (KDR; the Catalytic Domain of the VEGF Receptor)
In this standard pharmacological test procedure, KDR protein is mixed, in the presence or absence of an inhibitor compound, with a substrate peptide to be phosphorylated (a copolymer of glutaric acid and tyrosine, E:Y=4:1) and other cofactors such as Mg++ and sodium vanadate (a protein tyrosine phosphatase inhibitor) in an appropriate buffer to maintain pH (7.2). ATP and a radioactive tracer (either P32- or P33-labeled ATP) is then add to initiate phosphorylation. After incubation, the radioactive phosphate associated with the acid-insoluble fraction of the assay mixture is then quantified as reflection of substrate phosphorylation. This radioactive format was used to identify inhibitors of KDR tyrosine kinase activity where the IC50 is the concentration of drug that inhibits substrate phosphorylation by 50%. As an example, the compound of Example 66 inhibits KDR with an IC50 of 33.9 xcexcg/ml.
Mitogen Activated Protein Kinase (MAPK) Assay
To evaluate inhibitors of the MAP (mitogen activated protein) kinase a two component coupled standard pharmacological test procedure, which measures phosphorylation of a serine/threonine residue in an appropriate sequence in the substrate in the presence and absence of a putative inhibitor, was used. Recombinant human MEK 1 (MAPKK) was first used to activate recombinant human ERK2 (MAPK) and the activated MAPK (ERK) was incubated with substrate (MEP peptide or MYC peptide) in the presence of ATP, Mg+2 and radiolabeled 33P ATP. The phosphorylated peptide was captured on a P 81 phosphocellulose filter (paper filter or embedded in microtiter plate) washed and counted by scintillation methods.
The peptide substrates used in the assay are MBP, peptide substrate (APRTPGGRR), or synthetic Myc substrate, (KKFELLPTPPLSPSRRxe2x80xa25 TFA. The recombinant enzymes used were prepared as GST fusion proteins of human ERK 2 and human MEK 1. Inhibitor samples were prepared as 10xc3x97 stocks in 10% DMSO and an appropriate aliquot was used to deliver either 10 ug/ml for a single point screening dose or 100, 10, 1, and 0.1 uM final concentration for a dose response curve. Final DMSO concentrations were less than or equal to 1%.
The reaction was run as follows in 50 mM Tris kinase buffer, pH 7.4 in a reaction volume of 50 ul. The appropriate volume of kinase buffer and inhibitor sample was added to the tube. Appropriate dilution of enzyme was delivered to give 2-5 ug recombinant MAPK (Erk) per tube. The inhibitor was incubated with MAPK (Erk) for 30 min at 0 deg. C. Recombinant Mek (MAPKK) (0.5-2.5 ug) or fully activated Mek (0.05-0.1 units) was added to activate the Erk and incubated for 30 min at 30xc2x0 C. Then substrate and gamma 33P ATP was were added to give a final concentration of 0.5-1 mM MBPP or 250-500 uM Myc; 0.2-0.5 uCi gamma 33P ATP/tube; 50 xcexcM ATP final concentration. Samples were incubated at 30xc2x0 C. for 30 minutes and the reaction was stopped by adding 25 xcexcl of ice cold 10% TCA. After samples were chilled on ice for 30 min, 20 xcexcl of sample was transferred onto P 81 phosphocellulose filter paper or, appropriate MTP with embedded P 81 filter. Filter papers or MTP were washed 2 times with a large volume of 1% acetic acid, then 2 times with water. The filters or MTP were briefly air dried before addition of scintillant and samples were counted in the appropriate scintillation counter set up for reading 33P isotope. Samples included a positive control (activated enzyme plus substrate); a no enzyme control; a no substrate control; samples with different concentrations of putative inhibitor; and samples with reference inhibitors (other active compounds or non-specific inhibitors such as staurosporine or K252 B).
The raw data was captured as cpm Sample replicates were averaged and corrected for background count. Mean cpm data was tabulated by group and % inhibition by a test compound was calculated as (corrected cpm control-corrected. cpm sample/control)xc3x97100=% inhibition. If several concentrations of inhibitor were tested, IC50 values (the concentration which gives 50% inhibition) were determined graphically from the dose response curve for % inhibition or by an appropriate computer program The results obtained for representative compounds of this invention are listed in TABLE 3 where there may be separate entries for the same compound; this is an indication that the compound was evaluated more than one time.
Inhibition of Cancer Cell Growth as Measured by Cell Number
Human tumor cell lines were plated in 96-well plates (250 xcexcl/well, 1-6xc3x97104 cells/ml) in RPMI 1640 medium, containing 5% FBS (Fetal Bovine Serum). Twenty four hours after plating, test compounds were added at five log concentrations (0.01-100 mg/ml) or at lower concentrations for the more potent compounds. After 48 hours exposure to test compounds, cells were fixed with trichloroacetic acid, and stained with Sulforhodamine B. After washing with trichloroacetic acid, bound dye was solubilized in 10 mM Tris base and optical density was determined using a plate reader. Under conditions of the assay the optical density is proportional to the number of cells in the well. IC50s (concentrations causing 50% inhibition of cell growth) were determined from the growth inhibition plots. The test procedure is described in details by Philip Skehan et. at J. Natl. Canc. Inst., 82, 1107-1112 (1990). These data are shown below in TABLE 4. Information about some of the cell lines used in these test procedures is available from the American Type Tissue Collection: Cell Lines and Hybridomas, 1994 Reference Guide, 8th Edition. The Her2Neu cell line is a 3T3 line that has bbeen transfected with Her2 receptor kinase.
Based on the results obtained for representative compounds of this invention, the compounds of this invention are antineoplastic agents which are useful in treating, inhibiting the growth of, or eradicating neoplasms. In particular, the compounds of this invention are useful in treating, inhibiting the growth of, or eradicating neoplasms that express EGFR such as those of the breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary, or lung. The compounds of this invention are also useful in treating, inhibiting the growth of, or eradicating neoplasms of the breast that express the receptor protein produced by the erbB2 (Her2) oncogene. Additionally, the compounds of this invention are useful in treating or inhibiting polycystic kidney disease and colonic polyps.
The compounds of this invention may formulated neat or may be combined with one or more pharmaceutically acceptable carriers for administration. For example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solution or suspension containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 1000 mg/kg of animal body weight, optionally given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 1 to 1000 mg, preferably from about 2 to 500 mg. Dosage forms suitable for internal use comprise from about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
The compounds of this invention may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol.
The compounds of this invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
For the treatment of cancer, the compounds of this invention can be administered in combination with other antitumor substances or with radiation therapy. These other substances or radiation treatments can be given at the same or at different times as the compounds of this invention. These combined therapies may effect synergy and result in improved efficacy. For example, the compounds of this invention can be used in combination with mitotic inhibitors such as taxol or vinblastine, alkylating agents such as cisplatin or cyclophosamide, antimetabolites such as 5-fluorouracil or hydroxyurea, DNA intercalators such as adriamycin or bleomycin, topoisomerase inhibitors such as etoposide or camptothecin, antiangiogenic agents such as angiostatin, and antiestrogens such as tamoxifen.
The following representative examples show the preparation of the compounds of this invention.